The analytical chemistry and organic syntheses developed in this Project provide an essential underpinning for this Program. Experiments are designed to identify chemically-modified nucleotides formed by the reac- tions of certain chemotherapeutic agents and genotoxic compounds with native DNA. The mechanism and sequence specificity of cross-link formation will be investigated using sequence-defined duplex oligodeoxynucleotides. Exocyclic adducts, alkylation products, and cross-linked deoxynucleotides will be identified using advanced detection techniques of FAB mass spectro- metry, thermospray LC/MS, nuclear magnetic resonance, and high performance and liquid chromatography. In additional experiments, organic syntheses leading to single strand oligodeoxynucleotides of defined base sequence containing a single chemi- cally-modified site are proposed. Known exocyclic products of the reaction of DNA with BCNU, acrolein, and vinyl chloride, will be synthesized, converted to their phosphoramidites and incorporated into synthetic oligodeoxynucleotides using solid state techniques. New protecting groups for protection of the nucleoside phosphoramidites used in solid state DNA synthesis will be developed. This will permit the inclusion of the alkali- sensitive adducts into synthetic oligomers.